Acne vulgaris one of the most treated skin condition in the United States and other countries. Acne vulgaris is a commonly referred to simply as “acne” even though many other different and clinically distinct forms of acne are know. Acne affects many adolescents and adults.
The earliest evidence of acne is usually the formation of a sebaceous plug in the pores of hair follicles present in an individual's skin. Typically, sebaceous plugs are very small and not visible to the unassisted eye. A sebaceous plug may be formed when a combination of dead keratinocyte cells from the upper cornified layers of the skin and sebum block the opening of these skin pores. Bacteria such as Propionibacterium acnes (P. acnes) can then proliferate in skin pores occupied by a sebaceous plug. Meanwhile, the resulting plug of cells and sebum may adhere to the walls of the skin pore leading to the formation of an even larger plug in the pore and the subsequent widening of the pore. These enlarged plugs are called comedones and are commonly referred to as “blackheads” or “whiteheads.” Eventually, this enlargement can lead to the rupture of the pore walls and an inflammatory response. Once such a rupture has occurred, the body attempts to repair the skin and encapsulate the site of the inflammatory response by stimulating the growth of sheaths of cells out from the epidermis. However, the resulting encapsulation is often incomplete and may instead cause further rupture of the lesions that have been produced. This, in turn, can lead to the formation of multichanneled tracts as well as inflamed papules and inflamed pustules. These inflamed papules and inflamed pustules are commonly referred to as “pimples.”
Acne can produce scarring and is regarded as unesthetic and unattractive. As a result, the other effects of acne are often psychological, such as reduced self-esteem. To complicate matters, acne usually appears during adolescence, when many individuals already tend to be very socially insecure. Early and aggressive treatment is, therefore, advocated to lessen the physical and psychological impact of acne on individuals.
There are four main strategies for treating acne. These four treatment strategies are directed to one, or more, aspects of acne. One strategy is to correct an altered pattern of follicular keratinization that occurs during acne. A second strategy is to decrease sebaceous gland activity and sebum production. A third strategy is to decrease the size of the follicular bacterial population and, in particular, to decrease the number of P. acnes bacteria. A fourth strategy is to inhibit the production, or effects, of extracellular inflammatory mediators (such as cytokines inflammatory cells) to produce an anti-inflammatory effect. Importantly, the majority of these treatment strategies suffer from limited efficacy or undesirable side effects.
Several categories of compositions have been used to implement these different acne treatment strategies. Isotretinoin and vitamin A derivatives represent one such category of compositions. Isotretinoin reduces sebaceous gland size by decreasing the proliferation of basal sebocytes, decreasing sebum production by up to 90% and inhibiting sebocyte differentiation. Isotretinoin is available in dosage forms suitable for either topical or oral administration. Oral administration of isotretinoin has revolutionized the treatment of severe acne. This is because isotretinoin is the first drug able to alter follicular keratinization, alter sebum production, decrease the follicular bacteria population and produce anti-inflammatory effects. Unfortunately, isotretinoin is a known teratogen and can cause birth defects. A number of other serious side effects are also associated with isotretinoin treatment. These side effects include psychiatric disorders, such as depression and psychosis, as well as intracranial hypertension, acute pancreatitis, increased blood lipid levels, hearing impairment, neurotoxicity and inflammatory bowel disease.
Benzoyl peroxide and related compounds represents a second category of compositions used to treat acne. Benzoyl peroxide is one of the most commonly used agents for the treatment of topical acne. Benzoyl peroxide has strong anti-microbial properties, weak anti-inflammatory properties and weak anti-comedone properties. Benzoyl peroxide for acne treatment is provided in dosage forms such as creams, gels, foams, soaps or washes for topical application. These formulations typically contain from 2.5% to 10% benzoylperoxide. However, a number of side effects are also associated with benzoyl peroxide treatment including contact sensitivities such as burning, itching, peeling and swelling of the skin.
Anti-androgens and related compounds represent a third category of compositions used to treat acne. Androgens are steroidal sex hormones such as testosterone associated with the development of male characteristics. Inocoterone acetate, spironolactone, cyproterone acetate, flutamide and 5-alpha reductase inhibitors, such as finasteride, are examples of anti-androgens used to treat acne. The female steroidal sex hormone estrogen is another example of and anti-androgen. Anti-androgens bind androgen receptors in the body and inhibit their biological activity or produce biological effects opposite to those of androgens (such as estrogen). Treatment with anti-androgens inhibits the production of sebum to help control acne. However, anti-androgen treatment by oral administration, or other routes, is typically restricted to female patients. This is because male patients receiving anti-androgens can develop female secondary characteristics such as breast enlargement and may suffer a loss of male secondary sex characteristics. This loss of male secondary sex characteristics can include the loss of muscle mass, reduced activity of the male organs and reduced sexual desire. Altogether, this means there are serious limitations and side-effects associated with anti-androgen based acne treatment.
Antibiotics and other anti-microbial compounds represent a fourth category of compositions used to treat acne. Examples of antibiotics used to treat acne include clindamycin and erythromycin which can be administered orally, or topically, to reduce the population of bacteria on skin surfaces and within the pores. Antibiotics can decrease the numbers of P. acnes bacteria and other bacteria to reduce the production of potentially pore clogging fatty acids, such as the propionic acid produced by P. acnes bacteria, on the skin surface. This means that antibiotics can have both an anti-comedogenic effect (such as preventing the formation of “blackheads” and “whiteheads”) and can also help control the onset of inflammation resulting from the rupture of pore walls and the localized bacterial infection associated with this. However, a major limitation to the use of antibiotics to treat acne is an increase in the number of antibiotic resistant bacterial strains, including antibiotic resistant P. acnes strains, now in circulation.
As indicated above, sebum production plays a pivotal role in the pathogenesis of acne. Sebum production is known to promote the formation of comedones and increased sebum production is one of the early events that can contribute to the onset of acne.
Sebum is a mixture of relatively nonpolar lipids (such as oils, waxes and fats) which are mostly synthesized within the sebaceous glands. Secreted sebum provides a water-repellant, hydrophobic coating for the exterior surface of the skin. Thus, sebum normally helps lubricate and protect the skin.
Sebum is secreted by the sebaceous gland. The sebaceous glands are connected to hair follicles in the skin. The number of sebaceous glands in the skin remains approximately constant throughout the life of an individual, but the size of these glands tends to increase with age. Human sebaceous glands are a holocrine secreting tissues present in essentially all areas of the skin except for the palms and soles.
Holocrine secretions, such as sebum, result from the lysis of secretory cells in a gland. Holocrine secretions are first produced inside the secretory cells present in a gland. These secretory cells then rupture to release (secrete) the contents of these cells into the lumen, or interior space, of a gland.
In sebaceous glands, the cells responsible for the secretion of sebum are known as sebocytes. Sebocytes in the sebaceous gland fill with lipids and the other components of sebum. Sebocytes filled with these sebum components eventually lose their integrity and rupture. This causes the secretion of sebum by a sebaceous gland. Sebocytes filled with sebum have a characteristic, bubble-shaped cell morphology.
An increase in sebum secretion occurs in many people starting at about 9 years of age and continues to increase up to 17 years of age at which point the adult level of sebum secretion is typically reached. This period of increased sebum production is when most cases of acne occur. However, as discussed above, many of the strategies used to treat acne and control sebum production have undesirable side effects or other significant limitations. Sebum production also plays an important role in other conditions such as seborrhea (an abnormally increased secretion and discharge of sebum) as well as conditions in which dry and chapped skin develop.
Visfatin is an adipokine which is secreted by mature adipocytes. Visfatin is also called pre-B cell colony enhancing factor (PBEF), Nampt and nicotinamide phosphoribosyl transferase. Visfatin was initially reported as being secreted from visceral fat and was later reported to be secreted from subcutaneous adipocytes of the hypodermis. The hypodermis is a fat containing tissue located below the skin. The hypodermis also contains blood vessels and the basal (bottom) portion of hair follicles. Visfatin is also expressed by cells such as neutrophils and in tissues such as the liver, heart and muscle.
Visfatin is thought to be a visceral fat-derived hormone and has been reported by a Japanese group to mimic the biological activity of insulin both in vitro (˜in glass) on cultured cells and in vivo (˜in the living) by lowering plasma glucose levels in mice. However, this Japanese group later retracted their entire paper reporting these findings from the journal Science. The physiological role of visfatin is also unclear because the visfatin plasm concentration is 40-100 fold lower than that of insulin. Visfatin has also been reported to have enzymatic activity and can catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide. Importantly, the synthesis of nicotinamide mononucleotide is one step in the biosynthesis of the coenzyme nicotinamide adenine dinucleotide (NAD+).
This means the biological activities of visfatin and its role in physiological processes, such as the pathogenesis of acne and other conditions related to sebum production, are poorly understood. Importantly, visfatin may play a role in the pathogenesis of acne and other conditions, such as dry or oily skin, related to sebum production.
Thus, there is a need for improved compositions and methods that modulate visfatin activity to help treat acne and other conditions related to sebum production.